Pathophysiology of Diabetic Dyslipidemia

Abstract

Accumulating clinical evidence has suggested serum triglyceride (TG) is a leading predictor of atherosclerotic cardiovascular disease, comparable to low-density lipoprotein (LDL)-cholesterol (C) in populations with type 2 diabetes, which exceeds the predictive power of hemoglobinA1c. Atherogenic dyslipidemia in diabetes consists of elevated serum concentrations of TG-rich lipoproteins (TRLs), a high prevalence of small dense low-density lipoprotein (LDL), and low concentrations of cholesterol-rich high-density lipoprotein (HDL)2-C. A central lipoprotein abnormality is an increase in large TG-rich very-low-density lipoprotein (VLDL)1, and other lipoprotein abnormalities are metabolically linked to increased TRLs. Insulin critically regulates serum VLDL concentrations by suppressing hepatic VLDL production and stimulating VLDL removal by activation of lipoprotein lipase. It is still debated whether hyperinsulinemia compensatory for insulin resistance is causally associated with the overproduction of VLDL. This review introduces experimental and clinical observations revealing that insulin resistance, but not hyperinsulinemia stimulates hepatic VLDL production. LDL and HDL consist of heterogeneous particles with different size and density. Cholesterol-depleted small dense LDL and cholesterol-rich HDL2 subspecies are particularly affected by insulin resistance and can be named “Metabolic LDL and HDL,” respectively. We established the direct assays for quantifying small dense LDL-C and small dense HDL(HDL3)-C, respectively. Subtracting HDL3-C from HDL-C gives HDL2-C. I will explain clinical relevance of measurements of LDL and HDL subspecies determined by our assays. Diabetic kidney disease (DKD) substantially worsens plasma lipid profile thereby potentiated atherogenic risk. Finally, I briefly overview pathophysiology of dyslipidemia associated with DKD, which has not been so much taken up by other review articles.

Long-term safety and effectiveness of biosimilar insulin glargine in Japanese patients with diabetes mellitus in routine clinical practice: results of a post-marketing safety study

“…Serum lipids are known to be significantly impacted by insulin 24 . Hypertriglyceridemia is a common serum lipid abnormality associated with diabetes, due either to insulin resistance or deficiency.…”

Type 2 diabetes – unmet need, unresolved pathogenesis, mTORC1-centric paradigm

“…Dyslipidemia Most (60-90%) T2D patients are dyslipidemic [6][7][8]. T2D dyslipidemia triad (hypertriglyceridemia, increase in sdLDL-C, decrease in HDL-C) is driven by increase in VLDL-triglycerides (VLDL-TG) [141]. Increase in VLDL-TG is driven by hyperactive mTORC1 due to promoting hepatic steatosis, phosphatidylcholine synthesis [142], and disruption of the IR-Akt-FOXO1 pathway.…”

“…FoxO1 activation results in transcriptional activation of the microsomal TG transfer protein (MTP) [143] and apoCIII [144]. MTP combines the VLDL ingredients to form the lipoprotein particle, and apoCIII suppresses plasma VLDL-TG lipolysis by lipoprotein lipase [141]. Of note, T2D dyslipidemia is avoided upon knocking out the IR [59], implying an obligatory role for insulin in promoting T2D dyslipidemia [60].…”

Dissimilar Effects of Anagliptin and Sitagliptin on Lipoprotein Subclass in Standard or Strong Statin-Treated Patients with Type-2 Diabetes Mellitus: A Subanalysis of the REASON (Randomized Evaluation of Anagliptin versus Sitagliptin on Low-Density LipoproteiN Cholesterol in Diabetes) Trial

“…It has also been shown that the incidence of CAD differs by patterns of lipoprotein subclass [11]. For example, the atherogenic lipoprotein, small dense LDL-C (sdLDL-C), is often observed in patients with T2DM or insulin resistance [12]. Although the effects of antidiabetic agents on the patterns of lipoprotein subclass are assumed to be pivotal, an evaluation testing this assumption has not yet been performed in patients treated with DPP-4 inhibitors, which are among the most frequently prescribed antidiabetic agents [13,14].…”